P525: PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF ENTOSPLETINIB ADDED TO INTENSIVE INDUCTION AND CONSOLIDATION CHEMOTHERAPY IN NEWLY DIAGNOSED NPM1-MUTATED AML
Authors: J. C. Byrd, J. E. Cortes, M. D. Minden, T. Oellerich, E. M. Stein, J. Elder, P. Kumar, G. Bray, J. DiMartino, W. Stock
Journal: HemaSphere (2022)

Background: Spleen tyrosine kinase (SYK) is a component of both lymphoid and myeloid cell signaling pathways and is implicated in the pathogenesis of a subset of acute myeloid leukemia (AML) defined by dysregulated expression of HOXA9 and MEIS1 transcription factors. Entospletinib (ENTO) is an oral, selective SYK inhibitor that is acceptably tolerated when administered with intensive induction and consolidation in newly diagnosed AML patients (pts). In a Phase 2 study, following induction with cytarabine and daunorubicin (7 + 3) plus ENTO, higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) occurred in pts with rearrangements of the KMT2A gene (MLL-r) and mutations of the nucleophosmin 1 (NPM1) gene, both of which are associated with aberrant expression of HOXA9 and MEIS1, compared to pts without these mutations. In an exploratory analysis, pts with HOXA9/MEIS1 expression levels above the median experienced superior overall survival (OS) compared to pts with expression levels below the median. Aims: We hypothesize that the addition of ENTO to intensive induction/consolidation in newly diagnosed pts with NPM1-mutated AML will improve the CR rate without evidence of measurable residual disease (MRD-negative CR) post-induction and duration of event-free survival (EFS). Methods: AGILITY is a global, multi-center, double-blind, placebo-controlled trial of ENTO in combination with cytarabine plus daunorubicin or idarubicin induction (7 + 3) and age-adjusted high-dose cytarabine (HiDAC) consolidation in newly diagnosed AML pts aged 18–74 who are candidates for intensive induction and harbor a documented NPM1 mutation. Pts with co-mutated FLT3 are excluded. Pts will be stratified based on age (<60 vs ≥60 years) and anthracycline administered during induction (daunorubicin vs idarubicin). Approximately 180 pts will be randomized to receive 7 + 3 induction and HiDAC consolidation with ENTO (400mg orally twice daily) or with placebo. Pts with <5% leukemic blasts after induction cycle 1 will proceed to the first cycle of consolidation; pts with ≥5% residual blasts will undergo a second induction cycle. Pts who do not achieve CR after the last cycle of induction plus ENTO or placebo will be designated as induction treatment failures (ITF) for purposes of EFS estimation. Pts who achieve or remain in CR after 2 chemotherapy cycles (either 2 induction cycles or 1 induction and 1 consolidation cycle) will be evaluated for MRD in bone marrow based on enumeration of mutant NPM1 alleles using a molecular assay. Pts may receive ≤3 cycles of consolidation with HiDAC and ENTO or placebo per their original randomized treatment assignment beyond chemotherapy cycle 2. All pts will be followed for relapse and survival. The primary endpoint is the rate of MRD-negative CR (<0.01% mutant NPM1 alleles). A key secondary endpoint is EFS, defined as time from randomization to earliest occurrence of ITF, relapse from CR, or death from any cause. OS will be evaluated. Key exploratory endpoints will be the correlation between recurring genomic mutations and response or progression and longitudinal assessment of peripheral blood for detection of NPM1-m alleles among pts who achieve MRD-negative CR post-induction. Results: Trial in progress. Summary/Conclusion: Accrual is ongoing.